Utilizing MCF-7 human breast cancer cells as a model system, it is the objective of these investigations to relate certain changes in the functional and structural features of estradiol-17Beta (E2) to responses elicited by the receptor-ligand complex. Numerous reports have associated the various elements of such antiestrogen structures as tamoxifen with specific responses in target cells. Likewise, our preliminary experiments have suggested that particular structural components of E2 are responsible for certain responses in cancer cells. It is postulated that the change in tertiary structure of the estrogen receptor complex, brought about by specific alterations in the molecule of the estrogen ligand, results in quantitative and/or qualitative alterations in cellular responses. Specifically, it is the purpose of this project to synthesize a wide range of positional isomers of E2, as well as introduce additional functional groups into the natural estrogens. Precise changes in the structure of estrogen will be related to the stimulatory properties of the resulting receptor-estrogen complex. These experiments will examine the altered estrogens for their ability to bind to receptor and bring about "high affinity" nuclear uptake and "processing" of the complex. In addition, the estrogen analogue-receptor complex will be examined for its binding to specific regions of the chromatin acceptor site and to DNA. The capacity of each altered estrogen to elicit pS2 mRNA transcription and the induction of progesterone receptor, plasminogen activator and the 52KDa protein will be determined. Finally, the effect of each of the structural components of E2 on the growth of MCF-7 cells, as well as on their uterotrophic potency will be ascertained. The information is expected to provide insights to facilitate the development of agents which possess only the desired function of E2 for the treatment of hormone-dependent neoplasms or for use in fertility control without the undesirable side effects.